PROJECT SUMMARY Inflammatory bowel disease (IBD) is a chronic, relapsing condition with no cure. IBD is a therapeutic challenge due to lack of response to therapy, and side effects of medications including secondary infections and increased risk of malignancy. Furthermore, many IBD patients develop intestinal fibrosis, for which there is no effective medical therapy. When fibrosis occurs, patients undergo abdominal surgery for bowel resection. A medical approach that was both anti-inflammatory and anti-fibrotic would be extremely valuable in these patients, but is not currently available. Our previous studies have demonstrated that mast cells are key players controlling inflammation in IBD. In particular, mast cells have anti-inflammatory functions in chronic colitis even though they are proinflammatory in acute colitis. Based on high-throughput screens, we identified bone morphogenetic proteins (BMPs) as candidate molecules for the protective effect of mast cells. BMPs are anti-inflammatory cytokines that also have anti-fibrotic properties. We have demonstrated that mast cells produce BMPs upon chronic, but not acute, stimulation with inflammatory mediators. Our hypothesis is that mast cell-derived BMPs are critical anti-inflammatory factors that dampen inflammation, prevent fibrosis, and promote healing in IBD. Guided by strong preliminary data, the aims of this proposal are to 1) determine if BMPs are critical mediators of the anti-inflammatory effects of mast cells in colitis and 2) determine the role of BMPs in limiting fibrosis and promoting healing in chronic IBD. We expect that successful completion of this project will demonstrate the role of mast cell-derived BMPs as key anti-inflammatory, anti-fibrotic, and pro-healing mediators in the intestine. BMPs are already available therapeutically, but use has been limited by the short half-life and resultant high doses needed to achieve sustained effect. These experiments should lead to alternative approaches to target the BMP pathway, hopefully leading to the discovery of methods to cause sustained endogenous BMP upregulation in the intestine of patients with IBD. Optimistically, these results could lead to development of effective anti- inflammatory and anti-fibrotic medications. These findings may also be extrapolated to other chronic inflammatory conditions such as asthma.